DESCRIPTION: The Institute of Medicine has indicated that short-term, small scale randomized clinical trials (RCTs) should be conducted to establish the efficacy of testosterone replacement therapy (TRT) as a strategy to enhance muscular strength and reduce disability in clinical populations of hypogonadal men. Men with spinal cord injury (SCI) experience a high prevalence of hypogonadism which influences the neural, muscular, skeletal, and body composition deficits that occur after injury. In this regard, a single retrospective analysis has reported that TRT improved motor function in hypogonadal men with incomplete SCI. However, only one small prospective (open label) clinical trial has evaluated the safety/efficacy of TRT in men with SCI. This study reported that low- dose TRT improved lower extremity lean mass and reduced risk of sudden cardiac death in men with motor complete SCI, demonstrating that testosterone (T) safely improves lean mass even in the absence of voluntary muscle activity. However, body composition and bone mineral density (BMD) were unaltered in this study because these deficits respond only to higher-than-replacement T. Despite the potential benefits of TRT, clinical concern exists regarding the safety of this therapy, with increased hematocrit (which is rarely detrimental) and prostate enlargement being the only health risks proven by meta-analysis. Interestingly, the 5-reduction of T to dihydrotestosterone (DHT) mediates prostate enlargement, but this conversion is not required for the benefits of TRT. As evidence pharmacologic 5-reductase inhibition (via finasteride) ablates prostate enlargement in neurologically healthy hypogonadal men receiving higher-than-replacement T, without inhibiting the substantial musculoskeletal and lipolytic benefits of this treatment. However, the safety and efficacy of this novel combination therapy remains to be determined in men with chronic motor incomplete SCI. For this double-blind placebo-controlled RCT, hypogonadal men >18 years of age with chronic motor incomplete SCI (AIS C/D) who present with ambulatory dysfunction (0.20m/s - 0.80m/s on 10m walk test) will receive slightly higher-than-replacement T (125mg/week, i.m.) plus finasteride (5mg/day, p.o.) in FDA approved doses or vehicle/placebo for 12 months. We will assess: BMD and body composition via DXA, thigh muscle cross-sectional area (CSA) via MRI, maximal knee extensor (KE) torque via dynamometry, KE muscle activation via twitch interpolation, circulating markers of bone turnover and metabolic health, and safety measures including prostate health, hematocrit, and other putative health risks associated with TRT. Our primary hypotheses are that slightly higher-than-replacement T plus finasteride will safely 1) regenerate BMD in this population via antiresorptive actions, 2) enhance muscle CSA and improve neuromuscular force production, and 3) improve body composition. In order to test these hypotheses, the following Specific Aims will be evaluated: AIM 1: Evaluate the effects of 12 months of slightly higher-than-replacement T plus finasteride on bone mineral characteristics and bone turnover in hypogonadal men with motor incomplete SCI. AIM 2: Determine the effects of slightly higher-than-replacement T plus finasteride on the recovery of muscle integrity and neuromuscular force production in hypogonadal men with motor incomplete SCI. Exploratory AIM 3: Examine the effects of slightly higher-than-replacement T plus finasteride on body composition and the pathophysiology underlying metabolic syndrome in men with motor incomplete SCI. This proposal will provide the first-ever prospective clinical evidence evaluating whether higher-than- replacement T plus finasteride safely regenerates musculoskeletal integrity, enhances neuromuscular function, and improves body composition and metabolic health in hypogonadal men with motor incomplete SCI. These findings will benefit Veterans with SCI who experience musculoskeletal impairments and may provide the VA with a novel cost-effective therapy able to improve musculoskeletal and metabolic health in this population.